1-(3,4-Methylenedioxy-phenyl)-4,4-dimethyl-pent-1-en-3-ol

ABSTRACT

The compounds of the formula:   in which one of R1 and R2 is hydrogen and the other is hydroxyl, or R1 and R2 together represent oxygen, made by condensing piperonal with pinacoline and if desired reducing the ketone obtained to the corresponding alcohol, have interesting pharmacological properties, e.g., as potentiators of narcotics and analgesics.

United States Patent [191 Vallet [4 1 Oct. 7, 1975 l-( 3,4-METHYLEN EDlOXY-PHENYL )-4,4-

DlMETHYL-PENT-1-EN-3-OL [75] Inventor: Francois Marie Joseph Vallet, Paris,

France [73} Assignee: Unicler, Paris, France [22] Filed: Feb. 27, 1973 [21] Appl. No.: 336,242

[30] Foreign Application Priority Data Feb. 28, I972 France 72.06676 [52] US. Cl 260/340.5; 424/282 [SI] Int. Cl. C071) 317/54 [58] Field of Search 260/3405 [56] References Cited OTHER PUBLICATIONS Pace, Chem. Abstracts, Vol. 23, (1929), p. 4942.

Primary Examiner-James A. Patten Attorney, Agent, or F irm--Armstrong, Nikaido & Wegner ABSTRACT The compounds of the formula:

1 Claim, No Drawings 1 ,4-METHYLENEDIOXY-PHENYL)-4,4- DINIETHYL-PENT- 1 -EN- 3-OL The present invention provides the two new comwhich was bright yellow at the start, becomes paler and finally turns colourless at the end of the operation. A little acetone and water are finally added and the whole is heated to 50C to decompose-the excess borohypounds which are the 1-( 3,4-methylenedioxy-phenyl 5 dride. The solution is filtered if necessary and the prod- 4,4-dimethyl-l-pentene derivatives of the formula: uct is precipitated by adding water.

I-( 3,4-Methylenedioxy-phenyl )-4,4-dimethyl-pentl-en-3-ol (hereinafter referred to as D 306) forms a compact, white precipitate. On recrystallising it from ethanol, fine, colourless needles are obtained which H 7 melt at 74C. The yield is approximately 95%.

R R2 CH The two new compounds have been tested pharmacologically. in which one of R and R is hydrogen and the other is acute toxicities, detenlnll'led by the hydroxyl or R1 and R2 together denote oxygen Probits method, as the LD 50 s in mg/kg are as fol- According to a feature of the invention, these comlows: pounds are prepared by condensation of pinacoline and piperonal in an alkaline aqueous medium. This gives Compound Animal Meh 0d administration the ketone, which may then, if desired, be reduced to m the alcohol by a method known for converting ketones to alcohols. Preferably the reduction is effected with f g:g 1,250 potassium borohydride. Rats 300O 1,050

The following Examples illustrate the invention.

EXAMPLE 1 A mixture of 20 g (0.2 mol) of pinacoline and g The.chronic toxicity f l E L 2 i g es:- (0.2 mol) of piperonal dissolved in 50 ml of ethyl alcogated m rats (30 l divided mto ate es 0 e ho] is added continuous] to a mixture of 600 ml of compound was aclmmlstered at the rate of or 250 y d se) sus nded in water to water and 40 g of NaOH, cooled to ambient tempera- 3o mglkglday 10 animals per 0 pe d d H f th t which carboxy-methyl-cellulose had been added, with ture Stme magnetic? lmng O we 15 10 control animals receiving only carboxymethylcommued at ordinary temperature for a mmlmum cellulose. The experiment lasted for 8 weeks and then 10 days (generny days) After a few days an Olly half of the animals were observed for 2 weeks after layer forms which becomes ,more more f stopping the treatment. The weight curves of the then sets SOIICI and splits up mto SOIld lumps. Stirring is treated animals were normal comparable to those continued the solid masses break up of their own of the control animals. Likewise,'haematological examo o to give a heavy bright yellow homogeneous inations revealed only an increase in polynuclear neu- Preclpltate trophils at both doses. After stopping for 2 weeks, the

This precipitate is filtered off and recrystallised from 40 picture returned to normaL ethanol The Product, Y Y'P Y Macroscopic and microscopic examinations did not l y -p (herelmlfter referred to reveal significant lesion in the organs examined. as D 305 forms yellow needles and melts at The The alcohol D 306 was subjected to a large number yield is approximately 75%. of experiments to determine its effect on the central nervous s stem. The techni ues a lied, the doses ad- EXAMPLE 2 ministered the methods of dmini i ration, the animals 23.2 g (0.1 mol) of the ketone produced in Example used and the results obtained are given in Table [which 1 are dissolved in 200 ml of methanol, in an Erlenfollows; in this table, pdenotes the probability factor in meyer flask with a magnetic stirrer, and 5.4 g (0.1 mol) relation to the differences observed between the results of potassium borohydride and then added slowly, in relating to the treated animals and the results relating small portions. As the addition proceeds, the solution, to the control animals.

TABLE I CENTRAL NERVOUS SYSTEM Experiment Dose, mg/kg Administration Animals Results INVESTIGATION OF BEHAVIOUR Equilibrium and muscular tonus Turning rod (Boissier, Actualities Pharmucologiques, l2th series, p. l) and 200 intraperitoneal mice none traction (ibid) 100 and 200 intraperitoneal mice ditto chimney (Boissier, Med. exp., 1960, 3, 81-84) 100 and 200 intraperitoneal mice ditto Curiosity Anxiety-exploratory activity Plate with holes (Boissier. Arch. Int. Pharm., 1964, 147, 372-388) 100 and 200 intraperltoneal mice ditto evasion (Boissier, Therapie, I965. XX, 895-905) 30, I00 and intraperitoneal mice ditto "Open field or 50 and 100 intraperitoneal rats ditto TABLE I Continued CENTRAL NERVOUS SYSTEM Experiment Dose, mgjkg Administration Animals Results situation inducing anxiety (Fontenay,

J. Pharmacol. Paris, I970, I,243-254) 200 intraperitoneal rats decrease in activity 55% relative to the controls Aggressivencss 50, I and intraperitoneal rats none battle caused by electric shock (Brunaud, 200

International Neuropharmacological IO oral rats 227: increase in Conference, Rome. I958) aggressiveness Catalepsy 3 bungs technique (Courvoisier, I00,20() and intraperitoneal rats none Psychotropic drugs, Elsevier Pub. 250

Company, I957, 373) Loeomotor activity (Psychopharmacologie, Berl., I4, I969, 50 and I00 intraperitoneal mice none resistance to fatigue; swimming experiment (Laborit, C .R. Soc. Biol., I00 intraperitoneal young 64% decrease in I957, No. 7, p. I383) rats fatigue Neuro-muscular preparation (Coullant, 1,000 intraperitoneal rats activity 0. IO,

C.R. Soc. Biol., I970, I64, No. 4, P 0.05;

p. 709) which corresponds to average activity Hypnosis (Boissier, Act. Pharmacologi- I00, 200 and 300 intraperitoneal mice none ques, l2th series, p. I) 800 oral mice none Anti-convulsive action (Boissier,

Actualites Pharmacologiques, l2th series, page I) Electric shock 200 intraperitoneal rats Up to IOOVI protection against complete crisis,

Cardiazolc I00 intraperitoneal mice mortal crisis retarded by 6371,

P 0.035, 200 intraperitoneal mice 40% protection,

Styrchnine 200 intraperitoneal mice 55% protection Hypothermia-inducing activity 200 intraperitoneal mice Average hypothermia of 3C 50 and 75 oral mice Average hypothermia of IC Anti pyretic activity 200 intraperitoneal rabbits none Analgesic activity (Wooll'e and MacDonald, J. Pharmacol. 200 intraperitoneal mice Analgesic action Exp. Therap, I944, 80, 300-307) 6871, minutes D. 306 alone after the injection 4471, 40 minutes after the injection 07!, 80 minutes after the injection D. 306 codeine 200 intraperitoneal mice Reinforcement of the activity of Codeine:

+ 2771 20 minutes after the injection 4271, minutes after the injection 54%, 80 minutes after the injection D. 306 dextromoramide I00 I- 0.3 intraperitoneal mice Reinforcement of the activity of dextromoramide 40%, 20 minutes after the injection 6571, 40 minutes after the injection 7072, 60 minutes after the injection 527:, 80 minutes after the injection Accustoming (hypothermia) 6 ingestions oral mice No accustoming of mg/kg over I7 days Isolated mice test (Sofia, Life Sciences, I969, vol.8,

part. I, p. 705-716) 200 intraperitoneal mice 42% decrease in aggressiveness I0 intraperitoneal mice 7971 increase in aggressiveness INTERFERENCE WITH CHEMICAL AGENTS a) Hexobarhital (70 mg/kg) 25 intraperitoneal mice 88%, P 0.001

Potentiation of narcosis 50 intraperitoneal mice +I8I71, P U.()0I

I00 intraperitoneal mice +3 14%, P 0.00I

I50 intraperitoneal mice +638?! P 0.00I

25 oral mice 5071 P=0.006

5O oral mice +I 71 P 0.00I

I00 oral mice 5 +2289 P 0.00I

200 oral mice +268?! P ().00l

Ratio toxic dose Hexo (alone) ratio 4 active dost Hexo (together with D306) ratio 6.4 50 intraperitoneal mice +I I9/r, 0.0I P 0.00I

b) Methaqualone I00 mg/kg Potentiation of narcosis TABLE l Continued CENTRAL NERVOUS SYSTEM Experiment Dose. mg/kg Administration Animals Results c) Reserpine 25 X 2 intraperitoneal rats none Blepharospasm 100 X 2 ditto 200 X 2 ditto d) Amphetamine I00 intraperitoneal mice ditto Group toxicity I50 ditto 200 ditto e) Tremorine 10 mg/kg I50 intraperitoneal mice Partial inhibition of the effects of tremorine 200 intraperitoneal mice Partial inhibition of the effects of tremorine f) Eserine 50 intraperitoneal mice none I00 and 200 intraperitoneal mice ditto g) Ascorbic acid 50 intraperitoneal mice Excitation Nervousness In the case of the ketone D 305, the following results were obtained.

It is apparent from the above tables that the two compounds D 305 and D 306 do not possess any hypnotic or tranquilising action of their own but that they have a very significant potentiating effect on narcosis induced by hexobarbital and by methaqualone and on analgesia induced by codeine and by dextromoramide.

They possess anti-convulsive activity (electric shock, cardiazole) and show marked activity in the swimming experiment (muscular fatigue experiment).

The two compounds thus possess a nervous tropism from depressive tendencies and even dispel anxiety, and they also possess anti-convulsive activity.

They can be used especially as complementary substances in the treatment of anti-social states, as anxietydispelling and anti-depressive agents.

The invention includes within its scope pharmaceutical compositions which comprise one or both of the compounds of the invention in association with a compatible pharmaceutically acceptable carrier. Such compositions may be in a form suitable for oral administra tion or for endorectal administration. For example tablets, dragees or gelatine-coated pills may contain lOO to 300 mg of the ketone D 305 or of the alcohol D 306.

I claim:

1. 1 3 ,4-Methylenedioxy-phenyl )-4,4-dimethylpentl-en-3-ol. 

1. 1-(3,4-METHYLENEDIOXY-PHENYL)-4-4-DIMETHYLPENT-1-EN3-OL. 